Cytotoxicity of fluoroethylating Agents Is Potentiated by O^6-Benzylguanine

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概要

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• O^6-Benzylguanine (BG) is a potent depleter of a repair enzyme O^6-alkylguanine-DNA alkyltransferase. Pretreatment of cells with BG potentiates the cytotoxicity of chloroethylating anti-center agents. In this study we used HeLa S3 cells to examine the cytotoxic potentiation of 39 compounds after BG pretreatment. Compounds tested included anti-cencer agents and carcinogens, and among them only the cytotoxicity of methylating, chloroethylating and fluoroethylating agents was potentiated. This in the first description of the cytotoxic potentiation of fluoroethylating agents. Potentiation ratios were found to vary even among compounds possessing the same alkylating group. By pretreatment with 10 μM of BG, the cytotoxicity of methylating agents such as N-methyl-N-nitrosourea and streptozotocine was potentiated 3.7 and 9.4 fold, respectively. For chloroethylating agents, the potentiation ratios were 3.5 for N-chloroethyl-N-nitrosourea, 8.6 for N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N'-(2-chloroethyl)-N'-nitrosourea (ACNU), 2.2 for N, N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), 3.0 for N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU) and 5.2 for chloroethyl methanesulfonate. With respect to fluoroethylating agents, the potentiation ratios were 7.2 for N-fluoroethyl-N-nitrosourea, 2.0 for N-cyclohexyl-N'-fluoroethyl-N'-nitrosourea and 5.5 for fluoroethyl methanesulfonate. No effect was observed with the bromoethylating agent, N-bromoethyl-N-nitrosourea. There was no potentiation of the cytotoxicity of anti-cancer agents such as mitomycin C (MCC), cisplatin (CDDP), 5-fluorouracil (5FU), bleomycin (BLM), prednisolone, camptothecin, etoposide, methotrexate or vinblastine. A possible mechanism for the cytotoxic potentiation of the test compounds by BG pretreatment is discussed.

• 公益社団法人日本薬学会の論文
• 1996-07-15

著者

• Kohda Kohfuku

  Faculty Of Pharmaceutical Sciences Nagoya City Uniersity

• Terashima Isamu

  Faculty Of Pharmaceutical Sciences Nagoya City University

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• Mechanism of Formation of N^2-Benzylguanine in the Reaction of 2-Amino-6-chloropurine with Sodium Benzyl Oxide, and Benzylation of Nucleic Acid Bases
• Cytotoxicity of fluoroethylating Agents Is Potentiated by O^6-Benzylguanine

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